Interstitial Cystitis

Epidemiology, Pathophysiology, and

Clinical Presentation

Mary T. McLennan, MD

KEYWORDS
 Interstitial cystitis  Painful bladder syndrome
 Chronic pelvic pain  Urgency/frequency  Nocturia

KEY POINTS
 Interstitial cystitis is commonly underdiagnosed.
 Patients with lower abdominal/pelvic pain or discomfort should be specifically questioned
about associated symptoms such as frequency, urgency, and nocturia.
 Nocturia in a young patient is abnormal, and this should lead the clinician to rule out inter-
stitial cystitis as a possible cause for the pain.
 Dyspareunia is also common in these patients.
 There is a high association with other chronic pain conditions.
 The etiology is still unknown, although there may be a bladder mucosal defect plus either
central sensitization of the spinal cord or a sensory processing disorder.

INTRODUCTION

It is difficult to discuss a particular disorder when there is no universally accepted name

or definition of the disorder. Interstitial cystitis (IC) is recognized by providers as a
chronic painful bladder condition; however, it has several synonyms depending on
where in the world the physician practices and which organization defines the entity.
The National Institute of Diabetes and Digestive and Kidney Diseases defined IC by
strict criteria to ensure that consistent patient populations were studied, being
intended for research. The patient must have glomerulations or classic Hunner ulcers
on cystoscopic examination, and pain associated with either bladder filling or urinary
urgency. There must be at least 10 glomerulations per quadrant in at least 3 quadrants
after distention of the bladder was under anesthesia to 80 to 100 cm of water pressure
for 1 to 2 minutes. Presence of any of the criteria in Box 1 excludes the diagnosis of

The author has nothing to disclose.

Obstetrics Gynecology and Women’s Health, Saint Louis University School of Medicine, 6420
Clayton Road, St Louis, MO 63117, USA
E-mail address: [email protected]

Obstet Gynecol Clin N Am 41 (2014) 385–395

http://dx.doi.org/10.1016/j.ogc.2014.05.004 obgyn.theclinics.com
0889-8545/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
386 McLennan

Box 1
National Institutes of Health exclusion criteria

1. Bladder capacity greater than 350 mL on awake cystometry using either a gas or liquid
filling medium
2. Absence of an intense urge to void with the bladder filled to 100 mL gas or 150 mL water
during cystometry, using a fill rate of 30 to 100 mL per minute
3. The demonstration of phasic involuntary bladder contractions on cystometry using the fill
rate described previously
4. Duration of symptoms less than 9 months
5. Absence of nocturia
6. Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or
antispasmodics
7. A frequency of urination, while awake, of less than 8 times a day
8. A diagnosis of bacterial cystitis or prostatitis within a 3-month period
9. Bladder or ureteral calculi
10. Active genital herpes
11. Uterine, cervical, vaginal, or urethral cancer
12. Urethral diverticulum
13. Cyclophosphamide or any type of chemical cystitis
14. Tuberculous cystitis
15. Radiation cystitis
16. Benign or malignant bladder tumors
17. Vaginitis
18. Age less than 18 years

IC.1 Unfortunately, because of the diversity of symptoms it is apparent that such exclu-
sion criteria would exclude a large number of patients who likely have IC. Hanno and
colleagues2 reported that applying these strict criteria missed diagnosing more than
60% of patients regarded by experienced clinicians as definitely or likely having IC.
The American Urological Association (AUA) released its evidence-based guidelines
for IC/bladder pain syndrome (BPS) in the hopes of improving early diagnosis and
treatment. IC/BPS (both used) was defined as an “unpleasant sensation (pain, pres-
sure), perceived to be related to the urinary bladder, associated with lower urinary
tract symptoms of more than 6 weeks duration in the absence of infection or other
identifiable causes.”3 One can see from this definition that symptom duration is very
short, and this interpretation was deliberately selected to allow for treatment after a
relatively short period of symptoms. The Society for Urodynamics and Female Urology
concurred, stating that their definition constituted a clinical strategy and was not
intended to be interpreted rigidly.4
The International Society for the Study of Bladder Pain Syndrome defines the disor-
der as chronic pelvic pain, pressure, or discomfort perceived to be related to the uri-
nary bladder, accompanied by at least one other urinary symptom such as persistent
urge to void or urinary frequency. Confusable diseases as a cause of symptoms must
be excluded by history, physical examination, urinalysis, urine cultures, uroflowmetry,
postvoid residual, cystoscopy, and biopsy if indicated.5
 Interstitial Cystitis 387

The European Association of Urology (EAU) embraces the term BPS, recommend-
ing the term IC be reserved for a subset of patients with verified signs of chronic inflam-
mation extending submucosally, based at the time of cystoscopy, hydrodistention,
and bladder biopsy. It recommends that BPS is diagnosed on the bases of symptoms,
examination, urinalysis, and cystoscopy, with hydrodistention and biopsy. Pain should
be persistent or recurrent over a 6-month period to be defined as chronic. The char-
acter of the pain is key to the diagnosis, with pain typically related to bladder filling,
increasing with increased bladder volume, typically located suprapubically, but some-
times radiating to the groin, vagina, rectum, and sacrum. Pain is relieved by voiding but
returns shortly with further bladder filling. The EAU recognizes that the character of the
pain is key to the symptoms, and that patients typically have frequency and always
have nocturia. Although nocturia is a consistent symptom across age groups, its inci-
dence does vary with age, thus making this definition potentially exclusive to a certain
subgroup of patients (see later discussion of clinical presentation).6
A consensus panel in Asia defined IC as a disease of the urinary bladder, diagnosed
by 3 conditions: “lower urinary tract symptoms, bladder pathology, and exclusion of
confusable diseases.” The characteristic symptom of this complex is termed hyper-
sensitive bladder syndrome (HBS), which is defined as “bladder hypersensitivity usu-
ally associated with urinary frequency with or without bladder pain.” Included in this
was an algorithm for diagnosis and management of this condition.7
Irrespective of the definition the clinician adopts, there appear to be certain consis-
tencies across them: unpleasant sensation or chronic pain, and pressure or discom-
fort that is perceived to be related to the bladder accompanied by some other urinary
symptom, most notably urge to void, frequency, or nocturia. The biggest difference in
definition appears to be the time required to establish the diagnosis, which ranges
from 6 weeks for the AUA to “chronic” for the EAU (6 months). Cystoscopy is included
in most criteria to allow classification and further management strategies; however,
the AUA differs in that cystoscopy is listed as a consideration and not a requirement.
The AUA guidelines do not rely on the presence or absence of glomerulations; how-
ever, the presence of Hunner ulcers allows directed treatment.

PREVALENCE

Prevalence data are difficult to obtain because they depend on the definition, the pop-
ulation studied, and the method. Prevalence appears to have changed significantly
over the past 40 years or so. In a population-based study in 1975 the reported prev-
alence was 10 per 100,000 (0.01%), compared with 30 per 100,000 in (0.03%) in 1987
and 510 per 100,000 (0.5%) in 1994.8 In a cross-sectional study of the Boston area
from 2002 to 2005, the prevalence of painful bladder syndrome was 2.6%. The defi-
nition was based on self-report of pain which increased with bladder filling and was
relieved by urination present for at least 3 months.9 In 2011 Berry and colleagues10
published a study using 2006 United States census data. The random sample
included 131,691 adult females. Of these, 32,474 women reported having bladder
symptoms or diagnoses, of whom 12,752 completed the questionnaires. Depending
on the definition used, the prevalence ranged from 2.7% for a high-specificity defini-
tion (83% for distinguishing cases that did not have bladder pain syndrome from those
with other bladder and pelvic pain) to 6.5% for a high-sensitivity definition (81%
chance for identifying cases diagnosed with bladder pain syndrome). These percent-
ages translate into 3.3 to 7.9 million United States women 18 years or older with BPS/
IC symptoms.10 Only 9.7% of these patients reported being given a diagnosis of BPS/
IC, underscoring the potential for underdiagnosis.
388 McLennan

ETIOLOGY
Urothelial and Epithelial Dysfunction
In patients undergoing cystoscopy for potential IC, epithelial abnormalities can be
seen in the form of glomerulations and/or Hunner ulcers. The bladder urothelium is
lined by a protective layer of dense glycosaminoglycans (GAG), which maintains
impermeability to various solutes in the urine. The basic characteristic of this layer
is to provide mechanical and electrostatic defense against penetration by toxic,
acidic, or infective agents. This property is thought to be the basis of why the instilla-
tion of potassium (K sensitivity test) into the bladder of patients with IC will increase or
mimic the symptoms in most patients, an attribute that can also be seen in patients
with mucosal defects from radiation cystitis.11–14 However, studies have failed to
demonstrate any difference in the total GAG levels between controls and those with
IC.14,15 However, most GAG found in the urine appears to be produced in the upper
tract, so it is uncertain as to whether a difference would be expected to be found.

Tamm-Horsfall Protein
Tamm-Horsfall protein (THP) is an anionic protein that binds and neutralizes urinary
toxins, providing a protective function in the bladder. It is hypothesized that abnormal
THP proteins may play a role in the pathogenesis of IC. It has been demonstrated that
compared with normal subjects those with THP protein have reduced sialic acid con-
tent, which is critical to its protective activity.15,16 This deficiency may affect the
neutralization of toxic factors in the urine. There is additional evidence that the levels
of urinary cationic metabolites are higher in patients with IC and potentially cause
more damage to the bladder wall, resulting in a double insult.
Heparin and pentosan polysulfate have both been shown to neutralize toxic factors,
and this may help to explain their effect as going beyond simply that on the GAG layer
as initially thought.15,16

Mast Cell Activation

Biopsies of the bladder wall have demonstrated increased numbers and activation of
mast cells. These cells contain inflammatory mediators such as histamine, leukotri-
enes, serotonins, and cytokines.14,17 Mast cells are thought to potentially play a role
in frequency, pain, and fibrosis, and forms the basis for the use of antihistamines for
the treatment of IC.

Infection
Patients will often relate a history of having an acute urinary tract infection that initiated
pain, and that symptoms failed to resolve with antibiotics. However, culture-proven
urinary tract infections are found in the minority of patients.18,19 The potential sensiti-
zation of the bladder arising from the inflammation caused by a urinary tract infection
may be contributory, but its role remains unknown.

Antiproliferative Factor
Bladder epithelial cells of IC patients produce a novel antiproliferative factor (APF). The
normal bladder epithelium does not produce this factor in vitro. APF can inhibit the
proliferation of normal bladder epithelial cells, making it a possible cause of epithelial
thinning. It may alter the differentiation of tight junction formation and proliferation of
bladder epithelial cells, resulting in a decreased epithelial barrier. Moreover, APF de-
creases heparin-binding epidermal growth factor, which is important in the initiation of
cell migration for epithelial repair.20
 Interstitial Cystitis 389

Genetics
It has been reported in twin studies that there is a higher concordance of IC among
monozygotic than dizygotic twins. In addition, adult first-degree relatives of a patient
with painful bladder syndrome have a 17 times higher rate of IC than the general
population.21
Autoimmunity
The role of autoimmune deficiency has not been determined. However, CD81 and
CD41 lymphocytes, B lymphocytes, plasma cells, and immunoglobulins (IgA, IgG,
and IgM) have been found to be more prevalent in the bladder wall of IC patients
than in controls.22–24
Central Sensitization of the Spinal Cord
Because of the increased incidence of other chronic pelvic pain syndromes along with
IC, it has been theorized that all of these disorders may represent central sensitization
of the lower spinal cord. This proposition suggests that non–bladder-related syn-
dromes that cause pelvic pain would initiate sensitization in the lower spinal cord
such that the bladder was also perceived as a site of pain. This central sensitization
leads to upregulation in the dorsal horn such that the noxious stimulus may subse-
quently be removed while the pain is still perceived from the organ/origin. Upregula-
tion may also lead to a decreased threshold for activation, leading to perception of
pain at lower levels of stimulation. This inference might help to explain why patients
with IC have significant discomfort with very small bladder volumes in comparison
with normal subjects, and why patients still have pain after cystectomy. It also lends
validity to the use of neuropathic agents in the treatment of IC, especially those that
do not affect the bladder per se. However, it does not explain the association with
extrapelvic nonbladder pain syndromes such as chronic fatigue and fibromyalgia.21,25
Sensory Processing
As noted earlier, the close association with other chronic pain syndromes unrelated to
the pelvis is not adequately explained by a local bladder disorder or central sensitiza-
tion. An alternative hypothesis is that these patients have abnormal sensory process-
ing. It has been demonstrated that in patients undergoing thoracic surgery, those with
preexisting abnormal sensory processing continue to have chronic postoperative
pain. By contrast, patients having a hip replacement for hip osteoarthritis noted hyper-
analgesia in other sites normalized after replacement.25–27 Warren and colleagues25
have published an interesting article on the possible etiology and pathophysiologic
processes in nonbladder pain syndromes and IC.

CLINICAL PRESENTATION

Early teachings were that this was a disease of young, reproductive-age women. How-
ever, recent studies in multiple different countries have shown that it occurs across all
ages. In a diverse population in Denmark, the age at diagnosis ranged from 16 to
88 years, with a median age of 53 years.28 In a recent cohort of 3397 community-
dwelling women who met the RAND IC epidemiology case definition, age ranged
from 18 to 92 years, with a mean age of 45.7 years for a high-sensitivity case definition
and 46.4 years for a high-specificity definition.29
Symptoms tend to vary across age distributions. For those younger than 30 years
daytime frequency is the most common presenting symptom, followed equally by
dysuria and urgency. For those 30 to 50 years old, nocturia is most predominant
390 McLennan

followed by daytime frequency and dysuria, with dyspareunia and vulvar pain far less
frequent at approximately 20% lower rates than for the younger age group. For those
60 years or older, nocturia is the most frequent symptom. Dyspareunia and vulvar pain
occur with less frequency than either of the 2 younger groups (Table 1).30
In terms of key indicators for the practicing physician, nocturia in a young patient with
pelvic pain should raise the index of suspicion for IC. Rates range from 50% to 70%.28,30
It is also important that dyspareunia is reported in up to 60% of young patients.30 Pain is
not specifically related to intercourse, with 40% complaining of bladder pain after inter-
course and an equal number reporting exacerbation of bladder symptoms. Approxi-
mately one-third of patients may have pain located anywhere within the genital area.
In a study of 1469 patients who completed bladder-specific and general sexual
dysfunction questionnaires, Bogart and colleagues27 noted that the majority (88%)
with a current partner endorsed 1 or more symptom of general sexual dysfunction in
the previous 4 weeks. Bladder pain during and/or after sex was the most prevalent
symptom; however, 65% of patients reported lack of sexual interest. This percentage
is approximately double that of the general United States population.31 Only one-
fourth of these women had sought any medical help for this sexual dysfunction.
The classic description is pain that increases with increasing bladder volume and is
relieved temporarily by voiding. Warren and colleagues32 noted that 75% of patients
reported that pain was worse with filling; however, an additional 9% noted that their
pain improved with bladder filling. Two-thirds of reported pain was suprapubic
(83%), urethral (36%), genital (23%), and nongenital (23%).26
Urinary frequency is another consistent symptom across the various age groups,
with one study reporting 86% of patients having frequency greater than 11 times dur-
ing a 24-hour period and 71% having nocturia 3 or more times at night.32 Other inves-
tigators reported nocturia occurring at least 4 times in 15% and 44% of cases.28
Up to 90% of patients report that certain foods and drinks may aggravate or flare
their IC. Friedlander and colleagues33 reported that questionnaire-based literature
suggests that citrus fruits, tomatoes, vitamin C, artificial sweeteners, coffee, tea,
carbonated alcoholic beverages, and spicy foods tend to exacerbate symptoms,
whereas sodium bicarbonate and calcium glycerophosphate (Prelief) tend to improve
symptoms. Chocolate, coffee, and tea have also been noted to be problematic for
some patients, although the exact mechanism is uncertain. Alcohol also seems to
be a trigger, and in one study 94% of patients reported worsening of symptoms after
drinking an alcoholic beverage.33 White wine seems to be better than red, light beer
better than dark, and whiskey and brandy better than tequila and vodka. Lists of foods
can be found on various Web sites. As there is such a variability between patients, the

Table 1
Variation with age

<30 y 30–59 y >60 y

Urgency 73 56 52
Frequency 79 55 58
Dysuria 73 42 52
Nocturia 49 64 76
Dyspareunia 62 30 23
Vulvar pain 47 27 21

Data from Hanno PM, Landis JR, Matthews-Cook Y, et al. The diagnosis of interstitial cystitis revis-
ited: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol
1999;161(2):553–7.
 Interstitial Cystitis 391

author would typically recommend that if the patient ingests a particular food or
beverage on the “bad list” they should desist for 1 week, see if it makes any difference
to their symptoms, and if not add it back and sequentially delete another. The alterna-
tive is to cut everything out and then gradually add them back a week at a time; how-
ever, this is often very prohibitive for patients, as the list is so inclusive and compliance
poorer than when asking them to eliminate one item at a time.

ASSOCIATION WITH NONBLADDER PAIN SYNDROMES

There have been numerous and consistent reports on the association of IC with other
chronic pain conditions. However, it is difficult to discern the antecedent disorder that
may point to a common etiology or trigger.

Fibromyalgia
It has been reported that 9% to 12% of patients with IC also experience fibromyalgia,
and that 2.25% to 27% of patients with fibromyalgia have symptoms consistent with
IC.34 Nickel and colleagues24 noted in a case-control study a high association
between IC and fibromyalgia at approximately 18% versus 70.7%. In a recent
question-based screening for 4 different pain conditions in the Michigan Women’s
Health study, the odds of having fibromyalgia with a diagnosis of IC was 5.1 (95% con-
fidence interval [CI] 3.2–8.1).35 In a case-control study of 313 patients with urologic
symptoms/signs and characteristics of IC compared with matched controls, fibromy-
algia, chronic fatigue syndrome, irritable bowel syndrome, and Sicca syndrome were
consistently associated with one another. Seventy-eight percent of the patients with
IC had more than 2 syndromes, compared with 45% of the control group. The inves-
tigators concluded that there were 3 possible explanations: (1) there was no direct
relationship but there was sharing of a genetic or environmental risk factor; (2) based
on the antecedent syndrome itself, the other syndromes were a risk factor for devel-
opment of IC; and (3) the particular syndrome and IC were different manifestations of
the same pathophysiology or disease.36

Chronic Fatigue
In the study of twin discordant pairs for various definitions of chronic fatigue, the
fatigued twin was 20 times more likely to have IC than the nonfatigued twin.34 Nickel
and colleagues24 reported chronic fatigue in 9.5% of those with IC versus 1.7% in con-
trols matched for age. Warren and colleagues37 also noted that antecedent nonblad-
der syndromes appear to be a risk factor for IC. The odds ratio of IC with chronic
fatigue syndrome was 2.5, which was similar to that of all the chronic pain syndromes
(2 and 2.9). The odds ratio of IC also increased with an increasing number of ante-
cedent nonbladder pain syndromes.

Irritable Bowel
In one study of those with vulvodynia and other chronic comorbid pain conditions, those
with irritable bowel had an odds ratio of 6.1 (95% CI 4.0–9.4) of having IC.35 In a compar-
ative study of the prevalence of nonbladder syndromes in IC patients versus matched
controls, the odds ratio of irritable bowel based on self-reported physician diagnosis
was 3.6 (95% CI 2.3–5.6) and 2.9 (95% CI 1.9–4.5) based on symptoms.36 In a review
of 1037 full-length published articles from 1966 to April 2008, Rodriguez and col-
leagues34 reported that depending on the methodology used, between 7% and 48%
of patients with IC or symptoms of BPS had irritable bowel, and patients with IC were
11 times more likely than controls to be diagnosed with irritable bowel. The most robust
392 McLennan

evidence for overlapping conditions existed between these 2 particular conditions, and
the results were consistent across numerous studies and publications.

Other Gynecologic Pain Conditions

There has been an increase in reported association of other gynecologic syndromes
with IC. A recent publication from a large vulvar center noted that the odds of
screening positive for vulvodynia increased 2.3- to 3.3-fold when women reported
having any of the 3 other chronic pain conditions (IC, irritable bowel, fibromyalgia). Pa-
tients with vulvodynia were also more likely to have IC or irritable bowel as their sole
comorbidity.26 However, it is difficult to discern whether this represents true vulvody-
nia or if it is referred pain of bladder origin.
Warren and colleagues36 reported that after the onset of IC, 27% of their patients
reported burning genital pain that worsened with touch, tampons, and coitus, which
is consistent with vulvodynia; however, they considered this was best explained as
referred pain. No explanation as to why the investigators believed it was “referred”
was given.
In an interesting study during which patients were asked to map their pain on a
whole-body diagram, IC patients reported greater frequency of pain in almost all
body areas in comparison with controls. Twenty-seven percent of patients reported
pain in what was described as the primary IC site (vagina, lower abdomen, lower
back, pelvis, and buttock) while 23% reported primary pain site plus pain in 1 to 3
additional locations, 24% in 4 to 9 additional locations, and 26% in greater than 10
additional locations. In addition, they reported more severe sensory pain than the con-
trols, and this increased further when pain was reported in more than 3 locations. IC
patients also had higher scores on catastrophizing and depression. The investigators
opined that as 73% of patients reported pain at an area outside of the primary IC, this
indicated there may be some centrally mediated mechanism for the pain.38
In a 10-year review of the gynecologic literature assessing the prevalence of bladder
pain and endometriosis,39 the term “evil twin syndrome” was coined. The coexistence
of IC and endometriosis ranged from 16% to 78% (average 48%). These investigators
concluded that physicians who deal with patients with chronic pelvic pain need to
investigate for IC in patients with endometriosis.
In a study of an existing database of patients with IC, Warren and colleagues40
noted that in the 1 month before the diagnosis of IC, 38.7% of patients had a high inci-
dence of hysterectomy, oophorectomy, and other pelvic surgeries. The approximate
annual incidence of nonbladder pelvic surgeries was 15 times higher and that of hys-
terectomy 25 times higher than the incidence of the previous year, and higher than that
of controls. This high rate of surgery declined over the first 2 years after diagnosis.
Once the patient had a diagnosis of IC, surgery rates were markedly less, returning
to the levels of those of controls over 2 years. Although this is only one report, those
of us in clinical practice consistently hear from patients that they have had gynecologic
surgeries, notably hysterectomy or oophorectomy, for their pelvic pain and that their
pain was not relieved. This fact underscores the need for heightened awareness
that there are other causes of pelvic pain other than the reproductive organs. Treating
for IC or performing cystoscopy and hydrodistention are very low-level morbidity op-
tions compared with major gynecologic surgery.41

SUMMARY

For the practicing clinician, the important message is to consider IC/BPS in any patient
with persistent pelvic or lower abdominal discomfort, particularly in the setting of any
 Interstitial Cystitis 393

bladder symptom. This article underscores the importance of asking specifically about
pain with bladder filling, urgency, frequency, and nocturia, and placing this diagnosis
on the differential diagnosis of chronic pelvic pain. As there appears to be a high as-
sociation with other chronic pain syndromes, it is useful to ask about any history of fi-
bromyalgia, chronic fatigue, irritable bowel syndrome, endometriosis, and vulvodynia.

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